Differential response to keratinocyte growth factor receptor and epidermal growth factor receptor ligands of proliferating and differentiating intestinal epithelial cells

Abstract

The expression of the keratinocyte growth factor receptor (KGFR) has been analyzed on intestinal epithelial Caco-2 cells upon confluence-induced spontaneous differentiation. Western blot and immunofluorescence analysis showed that the expression of functional KGFRs, differently from that of epidermal growth factor receptor (EGFR), was up-modulated in post-confluent differentiated cultures compared with the pre-confluent cells. Confocal microscopy and immunoelectron microscopy revealed that the up-regulated KGFRs displayed a basolateral polarized distribution on the cell surfaces in the monolayer. In vivo immunohistochemical analysis on normal human colon tissue sections showed that KGFRs, differently from EGFRs, were mostly distributed on the more differentiated cells located on the upper portion of the intestinal crypt. Bromodeoxyuridine incorporation assay and Ki67 labeling indicated that the differentiated cells were able to proliferate in response to the two ligands of KGFR, KGF and FGF-10, whereas they were not stimulated by the EGFR ligands TGFalpha and EGF. Western blot and quantitative immunofluorescence analysis of the expression of carcinoembryonic antigen (CEA) in post-confluent cells revealed that incubation with KGF induced an increase of cell differentiation. Taken together these results indicate that up-modulation of KGFR may be required to promote proliferation and differentiation in differentiating cells and that, among the cells componing the intestinal epithelial monolayer, the target cells for KGFR ligands appear to be different during differentiation from those responsive to EGFR ligands.

Evaluation of in vitro cytotoxicity and paracellular permeability of intact monolayers with mouse embryonic stem cells

“…GFs are capable of inducing linear specific differentiation. For instance, EGF is a mitogenic polypeptide that allows or induces differentiation into ectoderm (including skin) and mesoderm (Gritti et al, 1999), while KGF is a cell-specific mitogen responsible for normal proliferation and differentiation of epithelial cells (Visco et al, 2004). The TGFβ family of proteins, including the activins and the inhibins, bind to different cell surface receptors with varying affinities.…”

“…Epidermal growth factor (EGF), and the related EGF family member, amphiregulin (AR), are mitogenic polypeptides that induce differentiation into ectoderm and mesoderm (Gritti et al, 1999). Keratinocyte growth factor (Kgf) is an epithelial cell-specific mitogen responsible for normal proliferation and differentiation of epithelial cells (Visco et al, 2004). In most cases, the growth factors were applied to aggregates of ES cells after removal of leukemia inhibitory factor (LIF), a cytokine that inhibits differentiation.…”

Novel xylan-controlled delivery of therapeutic proteins to inflamed colon by the human anaerobic commensal bacterium

“…The ability of B ovatus to use xylan as its sole energy source 15,16 and the inability of the human gut to digest xylan 17 probably contributes to their predominance in the colonic microbiota. It is likely that BO-KGF and BO-TGF delivers growth factors directly to the epithelium via diffusion or by receptors expressed on the basolateral surface of epithelial cells 18,19 made accessible as a result of compromised barrier function in the inflamed colon.…”

Expression of keratinocyte growth factor receptor correlates with expansive growth and early stage of gastric cancer

“…KGFR is expressed in epithelial cells throughout the gastrointestinal tract, and an intraperitoneal injection of KGF enhances normal intestinal epithelial growth (13,14). Regarding cancerous tissue, KGFR expression was previously reported in pancreatic cancer and colorectal cancer cells (15,16).…”